Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders in humans. In the United States, ADPKD is more common than cystic fibrosis, Huntington's disease, and muscular dystrophy. ADPKD is characterized by the formation of cysts in kidney and caused by mutation in either PKD1 (85%) or PKD2 (15%) gene. Tuberous sclerosis (TSC) is an autosomal dominant inheritable genetic disorder due to mutation in either TSC1 or TSC2 gene. TSC is characterized by formation of hamartomas in various tissues. Cyst formation in kidney is also observed in TSC. The PKD1 and TSC2 genes are located adjacent to each other on human chromosome 16p and deletion of both genes results in a contiguous gene syndrome responsible for the severe infantile polycystic kidney disease. TSC2 has been implicated to play a role in the proper functions of polycystin-1, the product of PKD1 gene. The long-term goals of this project are to understand the functional relationship between TSC2 and PKD1 and to elucidate the molecular mechanism of TSC2 in regulation of PKD1 function and ADPKD. The specific aims of this proposal are to elucidate the mechanism of TSC2 regulation by osmotic stress and to investigate the function of TSC2 in regulation of the plasma membrane localization of polycystin-1.